Blood gas/electrolytes calibrator and methods of making and using the same

ABSTRACT

Aqueous solutions containing buffers and electrolytes are adjusted to levels required for calibration of both blood gas analyzers and ion selective electrolyte analyzers. A control material, composed of similar matrix, is adjusted to three levels of blood gas and electrolyte conditions. These quality control materials are used to monitor blood gas/electrolyte laboratory instrumentation.

This is a continuation of application Ser. No. 07/359,250, filed May 31,1989, now abandoned, which is a division of application Ser. No.07/121,499, filed Nov. 17, 1987, now abandoned.

FIELD OF THE INVENTION

This invention relates to aqueous solutions containing buffers andelectrolytes adjusted to specific levels for calibration or qualitycontrol of chemical analyzers. In particular, this invention relates toa solution which has the specific parameters for the calibration andquality control of both blood gas and ion selective electrodeinstrumentation.

BACKGROUND OF THE INVENTION

Analytical devices capable of determining various parameters in wholeblood with the aid of ion-selective electrodes have been used inintensive care units and in the field of anaesthetics. Blood gases, suchas carbon dioxide and oxygen, can be measured using ion selectiveelectrodes. An ion selective electrode consists of an electrochemicalhalf-cell (an internal electrolyte solution and an internal referenceelectrode) and a sensing membrane. These types of electrodes are used tomeasure one type of ion in the presence of other ions in the bodilyfluids. To obtain accurate measurements, a set of calibration solutionsare used to calibrate the electrodes.

In addition to calibration, the tests run on clinical chemical analyzersare verified by specific control solutions. Under ideal conditions,control materials used in the verification of instrumentationperformance should have essentially the same constituents as thosepresent in the fluid which is to be subjected to analysis.

Most blood gas instruments are currently calibrated using a buffer forthe pH and humidified gases for carbon dioxide and oxygen. Someinstruments use tonometer buffer inside the instrument and use thisliquid for equilibration. Blood gas instruments that also measureelectrolytes have separate solutions for calibration and control of theion selective electrodes. The electrolyte calibrator and controlsolutions do not currently contain all the blood gas parameters.

BRIEF SUMMARY OF THE INVENTION

The present invention relates to calibrating and control solutions forinstrumentation which measures both blood gas and electrolytes and amethod of using such solutions with blood gas instruments. Thisinvention relates to aqueous solutions containing buffers andelectrolytes adjusted to specific levels for calibration or qualitycontrol blood gas instruments. In particular, the present inventionrelates to a novel blood gas-electrolyte instrument control solutionhaving three levels. The three levels simulate three different patientconditions: one normal and two abnormal. Level one has low electrolyteparameters, acidosis pH and gas parameters which represent respiratoryacidosis, i.e. low O₂ and high CO₂ concentrations. Level two has normalconditions in all parameters. Level three has high electrolyteparameters, alkalosis pH, and gas parameters which represent respiratoryalkalosis, i.e. low CO₂ and high O₂ concentrations.

Additionally, the present invention relates to a novel blood gaselectrolyte instrument calibrating solution that contains parametersnecessary for the calibration of both blood gas and ion selectiveelectrode instrumentation. In particular, the present calibratingsolution contains two levels having the necessary parameters. Level onehas normal pH, pCO₂ and pO₂ and electrolytes. Level two is the zerooxygen calibrator. It has physiologically high concentrations of CO₂,physiologically low electrolyte levels and zero O₂.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The blood gas-electrolyte calibrating solutions of this invention areprepared by conventional manufacturing techniques using readilyavailable materials. A typical calibrating solution with thecontemplation of this invention is prepared by simply combining inappropriate relative proportions buffer, electrolytes, and otherstandard auxiliary reagents.

EXAMPLE I

A Diamond Sensor System GEM 6 Blood Gas Electrolyte monitor iscalibrated with a calibrating solution having two levels. Thecalibrating solution is comprised of an aqueous biological buffer with apreservative, electrolytes, and blood gas components. A detergent isadded for use as a wetting agent.

Level one has normal pH, pCO₂, pO₂. Sulfate ions are used to keep thecalcium in solution. Level two is the "0" calibrator. It has low pH,physiologically high concentrations of CO₂ and zero O₂ andphysiologically low electrolyte levels. The O₂ is kept at zero, even inthe presence of room air, with sufficient sulfite and nitrogen.

                  TABLE I                                                         ______________________________________                                                        LEVEL 1 LEVEL 2                                               ______________________________________                                        NaCL (mMol/L)     --        46                                                CaCl.sub.2 (mMol/L)                                                                             3.8       0.3                                               KCL (mMol/L)      6.9       2.2                                               Sulfite (mMol/L)  --        40                                                Sulfate (mMol/L)  26        --                                                CO.sub.2 (mmHg)   35        65                                                O.sub.2 (mmHg)    115-170   0                                                 3-(N-Morpholino) propane                                                                        100       100                                               sulfonic acid (mMol/L)                                                        pH (37° C.)                                                                              7.4       6.9                                               Na.sup.+  (mMol/L)                                                                              135       150                                               K.sup.+  (mMol/L) 6.0       2                                                 Ca.sup.2+  (mMol/L)                                                                             2.0       0.2                                               CL.sup.-  (mMol/L)                                                                              120       80                                                Ionic Strength    160       160                                               ______________________________________                                    

Table I lists the composition of the two levels of the blood gaselectrolyte calibrating solution together with concentrations and pHvalues. The pH of the solution is adjusted and sodium bicarbonate isadded to reach the desired carbon dioxide level. Albumin may be added ifa protein matrix is desired.

The electrolytes used in this control solution may be: sodium,potassium, calcium, and chloride. Lithium is not added to thecalibrating solutions or controls for the DSS GEM 6 instrument due tointerference with the sensors, although, with other instruments lithiummay be used. The buffer used is designed to give the appropriate PHvalue by combining the acid and salt forms. This buffer was selected dueto the very small temperature effect demonstrated by the buffer. Varioussolutions having the above discussed levels can be prepared for as manycalibration points as necessary for the instrumentation. Hostinstrumentation use a one or two point calibration for slopingelectrodes.

The final solution is sterile filtered and is stored in gas tightcontainers without a gaseous headspace. In the final container nofurther equilibrium with gases will take place and the final solution istherefore not affected by pressure and temperature.

The addition of calcium as an electrolyte and bicarbonate as a bufferfor pH and carbon dioxide, creates conditions for the formation ofcalcium carbonate. Calcium carbonate is an insoluble precipitate, whichwill eventually remove all the calcium from solution and therefore makethe calcium no longer measurable as an ion. To prevent this fromoccurring sulfate ions are added which protect the calcium ion fromcontact with the carbonate ion. This protection is necessary when highlevels of both calcium and carbon dioxide are desired.

The Level I solution is tonometered with 100% nitrogen until the oxygenlevel is less than 10 mmHg. Sulfite ions are then added to scavenge theremaining oxygen. The sulfite is added in excess so that residualsulfite is available to scavenge oxygen that may contact the solution.This enables the solution to maintain a zero oxygen value. Thebicarbonate is then added to create the desired pCO₂ value.

The solutions are then tonometered using the appropriate gases needed toreach the requested oxygen and carbon dioxide values (the finalsolutions are sterile filtered and stored in gas tight containerswithout headspace). No further equilibrium with gases takes place andthe final solution is not affected by pressure and temperature. Thesolution is stable in the final container and is ready for use with ablood gas/electrolyte analyzer.

EXAMPLE II

The blood gas-electrolyte controls of this invention are prepared byconventional manufacturing techniques using readily available materials.A typical control within the contemplation of this invention is preparedby simply combining in appropriate relative proportions, buffer,electrolytes, foaming agent and other standard auxiliary reagents andchemicals; the pH and concentration of dissolved carbon dioxide thereofbeing adjusted to the appropriate value, depending on the natures, thecontrol, an aliquot thereof placed in a sealable receptacle; thereceptacle flushed with gas; and the receptacle sealed so as to create aheadspace above control fluids which is occupied by the gas. Albumin maybe added if a protein matrix is desired. Glycine is added to bind aportion of the calcium to provide a total calcium value that reflectsnormal values for Level II and abnormal values for Levels I and III. Theglycine also prevents precipitation of the remaining ionized calcium.

The performance of a Diamond Sensor Gem 6 Blood Gas-Electrolyte monitoris verified using a blood gas-electrolyte control. The controls arecomprised o& three levels: normal and two abnormal conditions. Levelone, an abnormal control, having low electrolyte levels, acidosis pH andgas levels which represent respiratory, acidosis, level two, normalparameters and level three, high levels of electrolytes, alkalosis pHand gas levels which represent respiratory alkalosis, were formed in thepresence of the biological buffer N-2-hydroxyethylpiperazine-N¹-2-ethane sulfonic acid. This buffer was selected due to the temperatureeffect demonstrated by the buffer. The temperature coefficient (changein pKa per degree C=0.014), enables the control to indicate amalfunction of the instrument temperature regulation. The material ispackaged in glass ampules which have been flushed with the appropriategases. This ampule must be shaken prior to use in a bloodgas-electrolyte analyzer. The shaking equilibrates the gas with theliquid and also creates a foam layer. The foam layer will protect thesolution from contamination with room air gases for 4 minutes afteropening the ampule.

                  TABLE II                                                        ______________________________________                                                     LEVEL 1 LEVEL 2   LEVEL 3                                        ______________________________________                                        NaCL (mMol/L)  41        48        79                                         CaCl.sub.2 (mMol/L)                                                                          2.1       2.9       3.4                                        KCL (mMol/L)   2.5       4.2       6.8                                        Glycine (mMol/L)                                                                             639       599       532                                        O.sub.2 (mmHg) 40        100       150                                        CO.sub.2 (mmHg)                                                                              60        40        13                                         N-2-hydroxyethylpiper-                                                                       50        50        50                                         azine-N'-2-ethane sulfonic                                                    acid (mMol/L)                                                                 pH (37° C.)                                                                           7.16      7.4       7.6                                        Na.sup.+  (mMol/L)                                                                           120       138       150                                        K.sup.+  (mMol/L)                                                                            2.5       4         6.8                                        Ca.sup.2+  (mMol/L)                                                                          0.9       1.15      1.5                                        Total Ca (mg/dl)                                                                             8.5       11.5      13.5                                       CL.sup.-  (mMol/L)                                                                           86        102       116                                        Tonic Strength 160       160       160                                        ______________________________________                                    

Table II lists the composition of the three levels of the bloodgas-electrolyte control solution together with concentrations and pHvalues.

The calibrator and control solutions are currently used to calibrate andcontrol the Diamond Sensor Systems GEM-6 blood gas electrolyte monitor.The two level calibrator solutions are used to perform two calibrationpoints on the instrumentation. The calibration points at 37 C. are:

    ______________________________________                                                                   HIGH                                               PARAMETER*  LOW CALIBRATOR CALIBRATOR                                         ______________________________________                                        pH          6.9 ± 0.02  7.4 ± 0.02                                      pCO.sub.2   65 mmHg ± 3.0                                                                             35 mmHg ± 3.0                                   pO.sub.2    0 mmHg ± 5.0                                                                              115 ± 5.0                                       K.sup.+     2.0 mM/L ± 0.3                                                                            6.0 mM/L ± 0.3                                  Ca.sup.++   0.2 mM/L ± 0.1                                                                            2.0 mM/L ± 0.1                                  ______________________________________                                         *Stated values are at atmospheric pressure, temperature coefficient of pH     = -.01 pH unit/C.                                                        

EXAMPLE 3

The control formulations by typical blood gas electrolyteinstrumentation. Table III shows the results of some of these tests.

                                      TABLE II                                    __________________________________________________________________________    Typical Values Expected                                                       Aqueous Blood Gas/Electrolyte Control                                         Parameter                                                                              Level                                                                             Instrument                                                                            Mean                                                                              Expected Range                                                                         1SD                                         __________________________________________________________________________    pH       I   Il 1303 7.16                                                                              7.14-7.18                                                                              0.002                                       pH       I   Corning 178                                                                           7.17                                                                              7.15-7.19                                                                              0.006                                       pH       I   NOVA Stat                                                                             7.15                                                                              7.13-7.17                                                                              0.001                                       pH       II  Il 1303 7.39                                                                              7.37-7.41                                                                              0.004                                       pH       II  Corning 178                                                                           7.41                                                                              7.39-7.43                                                                              0.002                                       pH       II  NOVA Stat                                                                             7.40                                                                              7.38-7.42                                                                              0.006                                       pH       III Il 1303 7.63                                                                              7.61-7.65                                                                              0.002                                       pH       III Corning 178                                                                           7.63                                                                              7.61-7.65                                                                              0.001                                       pH       III NOVA Stat                                                                             7.64                                                                              7.62-7.66                                                                              0.003                                       pCO.sub.2 mmHg                                                                         I   Il 1303 64  59-69    1.0                                         pCO.sub.2 mmHg                                                                         I   Corning 178                                                                           67  62-72    2.8                                         pCO.sub.2 mmHg                                                                         I   NOVA Stat                                                                             66  61-71    1.0                                         pCO.sub.2 mmHg                                                                         II  Il 1303 36  32-40    0.2                                         pCO.sub.2 mmHg                                                                         II  Corning 178                                                                           36  32-40    0.4                                         pCO.sub.2 mmHg                                                                         II  NOVA Stat                                                                             36  32-40    0.8                                         pCO.sub.2 mmHg                                                                         III Il 1303 11.0                                                                               9-13    0.1                                         pCO.sub.2 mmHg                                                                         III Corning 178                                                                           8.0  6-10    0.1                                         pCO.sub.2 mmHg                                                                         III NOVA Stat                                                                             11.0                                                                               9-13    0.1                                         pO.sub.2 mmHg                                                                          I   Il 1303 42  34-50    1.4                                         pO.sub.2 mmHg                                                                          I   Corning 178                                                                           41  33-49    2.0                                         pO.sub.2 mmHg                                                                          I   NOVA Stat                                                                             42  34-50    1.3                                         pO.sub.2 mmHg                                                                          II  Il 1303 104  96-112  2.0                                         pO.sub.2 mmHg                                                                          II  Corning 178                                                                           106  98-114  3.0                                         pO.sub.2 mmHg                                                                          II  NOVA Stat                                                                             102  94-110  3.9                                         pO.sub.2 mmHg                                                                          III Il 1303 180 172-188  2.5                                         pO.sub.2 mmHg                                                                          III Corning 178                                                                           183 175-191  3.1                                         pO.sub.2 mmHg                                                                          III NOVA Stat                                                                             189 183-199  2.5                                         Sodium mM/L                                                                            III NOVA 6  139 134-144  0.8                                         Sodium mM/L                                                                            III NOVA Stat                                                                             141 136-146  1.0                                         Sodium mM/L                                                                            III NOVA 10 144 139-149  1.0                                         Potassium mM/L                                                                         I   NOVA 6  2.4 2.1-2.7  0.1                                         Potassium mM/L                                                                         I   NOVA Stat                                                                             2.5 2.2-2.8  0.1                                         Potassium mM/L                                                                         I   NOVA 10 2.4 2.1-2.7  0.1                                         Potassium mM/L                                                                         II  NOVA 6  4.0 3.7-4.3  0.1                                         Potassium mM/L                                                                         II  NOVA Stat                                                                             3.8 3.5-4.1  0.1                                         Potassium mM/L                                                                         II  NOVA 10 3.8 3.5-4.1  0.1                                         Potassium mM/L                                                                         III NOVA 6  6.4 6.1-6.7  0.1                                         Potassium mM/L                                                                         III NOVA Stat                                                                             6.9 6.6-7.2  0.1                                         Potassium mM/L                                                                         III NOVA 10 6.5 6.2-6.8  0.1                                         iCa mM/L I   NOVA 6  0.8 0.6-1.0  0.1                                         iCa mM/L I   NOVA Stat                                                                             0.8 0.6-1.0  0.1                                         iCa mM/L II  NOVA 6  1.1 0.9-1.3  0.1                                         iCa mM/L II  NOVA Stat                                                                             1.1 0.9-1.3  0.1                                         iCa mM/L III NOVA 6  1.6 1.4-1.8  0.1                                         iCa mM/L III NOVA Stat                                                                             1.6 1.4-1.8  0.1                                         Chloride mM/L                                                                          I   NOVA Stat                                                                             96  93-99    0.4                                         Chloride mM/L                                                                          I   NOVA 10 96  93-99    0.2                                         Chloride mM/L                                                                          II  NOVA Stat                                                                             108 104-112  1.0                                         Chloride mM/L                                                                          II  NOVA 10 108 104-112  0.1                                         Chloride mM/L                                                                          III NOVA Stat                                                                             124 120-128  0.3                                         Chloride mM/L                                                                          III NOVA 10 124 121-129  0.1                                         Total Ca mg/L                                                                          I   NOVA 10 0.9 0.7-1.1  0.2                                         Total Ca mg/L                                                                          II  NOVA 10 1.0 0.8-1.2  0.2                                         Total Ca mg/L                                                                          III NOVA 10 1.8 1.6-2.0  0.2                                         Lithium mM/L                                                                           I   Corning Flame                                                                         0.6 0.4-0.8  0.3                                         Lithium mM/L                                                                           II  Corning Flame                                                                         1.7 1.5-1.1  0.3                                         Lithium mM/L                                                                           III Corning Flame                                                                         3.0 2.8-3.2  0.3                                         __________________________________________________________________________

While these calibrating and control systems are particularlyadvantageous in biological fluid analysis systems such as Diamond SensorSystems GEM®-6 it will be apparent that other biological fluid analysissystems can use the presently described calibrating and controlsolutions. Therefore, while particular embodiments of the invention havebeen shown and described, various modifications will be apparent tothose skilled in the art and therefore is not intended that theinvention be limited to the disclosed embodiments or to details thereofand departures may be made there from within the spirit and scope of theinvention.

What is claimed is:
 1. Blood gas-electrolyte calibrating solutionscomprised of an aqueous buffer, electrolytes and blood gas componentscomprising:(a) a first solution comprised of a sufficient amount of anaqueous buffer, electrolytes and blood gas components to obtain humanreference value pH, pCO₂, pO₂, higher than human reference valueelectrolyte concentration for K⁺ and Ca²⁺, and human reference valueelectrolyte concentration for Na, said first calibrating solution havingan ionic strength of about 160 mMol/l; and (b) a second solutioncomprised of a sufficient amount of an aqueous buffer, electrolytes andblood gas components to obtain human reference pH, higher than humanreference value of pCO₂, and pO₂ of OmmHg, said OmmHg being maintainedby adding a sufficient amount of sulfite, lower than human referencevalue electrolyte concentration for K⁺ and Ca²⁺ and higher than humanreference value electrolyte concentration for Na³⁰, said secondcalibrating solutions having an ionic strength of about 160 mMOL/l. 2.The calibrating solutions of claim 1 wherein the buffer is3-(N-Morpholino)propane sulfonic acid.
 3. Calibrating solutionscomprised of an aqueous buffer, electrolytes, and blood gas componentscomprising:(a) a first solution comprised of a sufficient amount of anaqueous buffer, electrolytes and blood gas components to obtain pH ofabout 7.4, pCO₂ of about 35 mmHg and pO₂ of 115-170 mmHg and electrolyteparameters of about 135 mMOL/l of Na⁺, 6.0 mMOL/l of K⁺, and 2.0 mMOL/lof Ca²⁺, said first calibrating solution having an ionic strength ofabout 160 mMOL/l, and (b) a second solution comprised of a sufficientamount of buffer, sulfites, electrolytes and blood gas components toobtain pH of about 6.9, pCO₂ of about 65 mmHg and pO₂ of O mmHg, said OmmHg being maintained by adding a sufficient amount of sulfite ions, andelectrolyte parameters of about 150 mMOL/l of Na⁺, 2.0 mMOL/l of K⁺, and0.2 mMOL/l of Ca²⁺, said second calibrating solution having an ionicstrength of about 160 mMOL/l.
 4. A method to calibrate an instrumentwith pH, blood gas, and electrolyte capacity comprising calibrating saidinstrument with solution of claims 1 or
 3. 5. A method to includecalcium in a calibration solution for an electrolyte instrument whereineither a bicarbonate buffer or CO₂ is also present in solutioncomprising adding, sufficient sulfate ions to prevent the formation ofcalcium carbonate to a calibrating solution including calcium.